2024
Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain
Vasylyev D, Zhao P, Schulman B, Waxman S. Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. The Journal Of General Physiology 2024, 156: e202413596. PMID: 39378238, PMCID: PMC11465073, DOI: 10.1085/jgp.202413596.Peer-Reviewed Original ResearchConceptsDorsal root ganglionGain-of-function Nav1.7 mutationsDorsal root ganglion neuronsSodium channel Nav1.7Inherited erythromelalgiaNav1.7 mutationsNeuropathic painNeuronal hyperexcitabilityOpen-probabilityVoltage-gated sodium channel Nav1.7Hyperexcitability of DRG neuronsModel of neuropathic painSubthreshold membrane potential oscillationsResting membrane potentialMembrane potential oscillationsReduced firing probabilityIncreased rheobaseNav1.8 channelsDRG neuronsHuman genetic modelsNav1.8Root ganglionNav1.7 channelsNav1.7AP generationTRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization
Gualdani R, Barbeau S, Yuan J, Jacobs D, Gailly P, Dib-Hajj S, Waxman S. TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2406186121. PMID: 39226353, PMCID: PMC11406256, DOI: 10.1073/pnas.2406186121.Peer-Reviewed Original ResearchConceptsLaser-assisted in situ keratomileusisPhotorefractive keratectomyOcular Surface Disease Index scoreCapsaicin-induced desensitizationPhotorefractive keratectomy enhancementDisease Index scorePhysiological membrane potentialsCorneal neuralgiaTRPV1 variantsCorneal painRefractive surgeryRefractive errorCapsaicin desensitizationPersistent painBradykinin sensitivityNerve injuryM mutationPatch clampChannel activitySurgical techniqueLeftward shiftInflammatory mediatorsM-channelPainIndex scoreDisordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders
Dib-Hajj S, Waxman S. Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders. Journal Of Clinical Investigation 2024, 134: e182198. PMID: 38949022, PMCID: PMC11213459, DOI: 10.1172/jci182198.Peer-Reviewed Original ResearchConceptsTetrodotoxin-sensitiveHyperexcitability disordersSensory neuronsExcitability of sensory neuronsGene therapy modalitiesPeripheral sensory neuronsVoltage-gated sodiumMinimal side effectsGene therapyInduce analgesiaTherapy modalitiesSide effectsTherapeutic strategiesNav channelsAttenuating excitationIn vivoHyperexcitabilityAnalgesiaNeuronsDisordersPainTherapyGenesBiodistributionRats
2023
Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes
Ghovanloo M, Tyagi S, Zhao P, Effraim P, Dib-Hajj S, Waxman S. Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes. Channels 2023, 18: 2289256. PMID: 38055732, PMCID: PMC10761158, DOI: 10.1080/19336950.2023.2289256.Peer-Reviewed Original ResearchConceptsSexual dimorphismRodent dorsal root ganglion neuronsBiophysical propertiesDorsal root ganglion neuronsExpression patternsSex-dependent regulationVoltage-gated sodiumFunctional analysisGanglion neuronsRodent sensory neuronsMouse dorsal root ganglion neuronsNaïve WT miceNumber of cellsMixed populationDimorphismUniform experimental conditionsSex-dependent differencesSensory neuronsNative DRG neuronsPain pathwaysDRG neuronsWT miceClinical studiesNav currentsAdult malesConditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury
Benson C, Olson K, Patwa S, Kauer S, King J, Waxman S, Tan A. Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury. Journal Of Neuroscience 2023, 44: e1670222023. PMID: 37963762, PMCID: PMC10851682, DOI: 10.1523/jneurosci.1670-22.2023.Peer-Reviewed Original ResearchConceptsSpinal cord injuryRate-dependent depressionΑ-motor neuronsGlutamate transporter 1Dendritic spine dysgenesisCord injurySpine dysgenesisDevelopment of SCIMild contusion spinal cord injuryAstrocytic glutamate transporter 1Glial-specific glutamate transporterContusion spinal cord injuryTransporter 1Development of hyperreflexiaMonosynaptic H-reflexDendritic spine densityPre-injury levelSpinal reflex circuitsVentral spinal cordReflex hyperexcitabilityHyperexcitability disordersFunctional recoveryGlutamate clearanceH-reflexVentral hornIncreased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia
Benson C, King J, Kauer S, Waxman S, Tan A. Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia. Journal Of Neurophysiology 2023, 130: 1358-1366. PMID: 37877184, PMCID: PMC10972632, DOI: 10.1152/jn.00234.2023.Peer-Reviewed Original ResearchConceptsSpinal cord injuryRate-dependent depressionTripartite synapsesGLT-1Astrocytic GLT-1 expressionChronic neurological complicationsGLT-1 expressionAstrocyte involvementChronic spasticityUninjured shamsNeurological complicationsNeuropathic painHyperexcitability disordersH-reflexPSD-95 proteinReactive astrocytesVentral hornCord injuryMuscle toneAstrocytes' roleSpinal cordSpinal circuitsSynaptic transmissionHyperreflexiaSpasticityIh current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain
Vasylyev D, Liu S, Waxman S. Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain. The Journal Of Physiology 2023, 601: 5341-5366. PMID: 37846879, PMCID: PMC10843455, DOI: 10.1113/jp284999.Peer-Reviewed Original ResearchConceptsFunction Nav1.7 mutationsDorsal root ganglion neuronsSmall DRG neuronsDRG neuronsNav1.7 mutationNeuropathic painGanglion neuronsHuman genetic modelsAction potentialsDRG neuron excitabilityDRG neuron hyperexcitabilityRodent DRG neuronsAP generationCardiac cellsPotential molecular targetsNeuron hyperexcitabilitySevere painPain therapeuticsCNS neuronsExcessive firingNeuron excitabilityCentral neuronsSubthreshold oscillationsHyperexcitabilityNeuronal firingNav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation
Wimalasena N, Taub D, Shim J, Hakim S, Kawaguchi R, Chen L, El-Rifai M, Geschwind D, Dib-Hajj S, Waxman S, Woolf C. Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation. Experimental Neurology 2023, 364: 114393. PMID: 37003485, PMCID: PMC10171359, DOI: 10.1016/j.expneurol.2023.114393.Peer-Reviewed Original ResearchConceptsParoxysmal extreme pain disorderSmall fiber neuropathyFunction mutationsDRG neuron hyperexcitabilityYoung adult miceVoltage-gated sodium channel NaSodium conductanceAge-related changesNeuron hyperexcitabilityPain disordersCongenital insensitivitySodium channel NaExcitability changesFemale miceMouse DRGYoung miceNeuronal excitabilityNoxious heatSkin lesionsVoltage-gated channelsAdult miceNeuron subtypesNervous systemProfound insensitivityMiceInflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity
Higerd-Rusli G, Tyagi S, Baker C, Liu S, Dib-Hajj F, Dib-Hajj S, Waxman S. Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2215417120. PMID: 36897973, PMCID: PMC10089179, DOI: 10.1073/pnas.2215417120.Peer-Reviewed Original ResearchConceptsCell biological mechanismsAxonal surfaceLive-cell imagingIon channel traffickingAnterograde transport vesiclesTransport vesiclesInflammatory mediatorsChannel traffickingPlasma membraneVesicular loadingIon channelsKv channelsPotential therapeutic targetPotassium channel KSodium channel NaTraffickingBiological mechanismsTherapeutic targetAbundanceRetrograde transportDistal axonsChannel NaInflammatory painNociceptor activityAxonal transport
2019
Rat NaV1.7 loss-of-function genetic model: Deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers
Grubinska B, Chen L, Alsaloum M, Rampal N, Matson D, Yang C, Taborn K, Zhang M, Youngblood B, Liu D, Galbreath E, Allred S, Lepherd M, Ferrando R, Kornecook T, Lehto S, Waxman S, Moyer B, Dib-Hajj S, Gingras J. Rat NaV1.7 loss-of-function genetic model: Deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers. Molecular Pain 2019, 15: 1744806919881846. PMID: 31550995, PMCID: PMC6831982, DOI: 10.1177/1744806919881846.Peer-Reviewed Original ResearchConceptsOlfactory functionNav1.7 proteinPain behaviorPain responseRat modelSmall-diameter dorsal root ganglion neuronsNormal intraepidermal nerve fibre densityIntraepidermal nerve fiber densityIntra-epidermal nerve fibersDorsal root ganglion neuronsNeuropathic pain behaviorsNeuropathic pain responsesSpinal nerve ligationNerve fiber densityDorsal root gangliaAction potential firingPeripheral nervous systemEarly postnatal developmentGenetic animal modelsNav1.7 lossNerve ligationPain targetsNeuropathic conditionsGanglion neuronsRoot ganglia
2018
Nonmuscle myosin II isoforms interact with sodium channel alpha subunits
Dash B, Han C, Waxman S, Dib-Hajj S. Nonmuscle myosin II isoforms interact with sodium channel alpha subunits. Molecular Pain 2018, 14: 1744806918788638. PMID: 29956586, PMCID: PMC6052497, DOI: 10.1177/1744806918788638.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnkyrinsBrainCell Line, TransformedElectric StimulationGanglia, SpinalGene Expression RegulationGreen Fluorescent ProteinsHumansImmunoprecipitationMiceMice, Inbred C57BLMice, TransgenicMolecular Motor ProteinsMyosin Heavy ChainsNAV1.6 Voltage-Gated Sodium ChannelNonmuscle Myosin Type IIBPatch-Clamp TechniquesRatsTransfectionConceptsSodium channel alpha subunitND7/23 cellsChannel alpha subunitDorsal root ganglion tissueAlpha subunitMyosin II motor proteinsNonmuscle myosin II isoformsRodent nervous tissueRodent brain tissueSteady-state fast inactivationVoltage-sensitive channelsFast inactivationVoltage-dependent activationSodium channel alphaGanglion tissueIsoform-dependent mannerMyosin II isoformsNervous tissueRecombinant myosinBrain tissueCommon structural motifRamp currentsMotor proteinsCellular excitabilitySodium channelsTherapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury
Guo Y, Benson C, Hill M, Henry S, Effraim P, Waxman S, Dib-Hajj S, Tan AM. Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury. Molecular Pain 2018, 14: 1744806918788648. PMID: 29956587, PMCID: PMC6053256, DOI: 10.1177/1744806918788648.Peer-Reviewed Original ResearchConceptsDendritic spine dysgenesisNeuropathic painSpine dysgenesisBurn injurySignificant tactile allodyniaDorsal horn neuronsChronic disease burdenActivity-dependent expressionCutaneous burn injurySecond-degree burn injuryBurn injury modelC-fos expressionPotential molecular targetsDrug discontinuationHeat hyperalgesiaTactile allodyniaDorsal hornPain outcomesChronic painNociceptive activityLower painDisease burdenInjury modelCognitive dysfunctionPain
2015
The Concise Guide to PHARMACOLOGY 2015/16: Overview
Alexander S, Kelly E, Marrion N, Peters J, Benson H, Faccenda E, Pawson A, Sharman J, Southan C, Buneman O, Catterall W, Cidlowski J, Davenport A, Fabbro D, Fan G, McGrath J, Spedding M, Davies J, Collaborators C, Aldrich R, Attali B, Bäck M, Barnes N, Bathgate R, Beart P, Becirovic E, Biel M, Birdsall N, Boison D, Bräuner‐Osborne H, Bröer S, Bryant C, Burnstock G, Burris T, Cain D, Calo G, Chan S, Chandy K, Chiang N, Christakos S, Christopoulos A, Chun J, Chung J, Clapham D, Connor M, Coons L, Cox H, Dautzenberg F, Dent G, Douglas S, Dubocovich M, Edwards D, Farndale R, Fong T, Forrest D, Fowler C, Fuller P, Gainetdinov R, Gershengorn M, Goldin A, Goldstein S, Grimm S, Grissmer S, Gundlach A, Hagenbuch B, Hammond, Hancox J, Hartig S, Hauger R, Hay D, Hébert T, Hollenberg A, Holliday N, Hoyer D, Ijzerman A, Inui K, Ishii S, Jacobson K, Jan L, Jarvis G, Jensen R, Jetten A, Jockers R, Kaczmarek L, Kanai Y, Kang H, Karnik S, Kerr I, Korach K, Lange C, Larhammar D, Leeb‐Lundberg F, Leurs R, Lolait S, Macewan D, Maguire J, May J, Mazella J, Mcardle C, Mcdonnell D, Michel M, Miller L, Mitolo V, Monie T, Monk P, Mouillac B, Murphy P, Nahon J, Nerbonne J, Nichols C, Norel X, Oakley R, Offermanns S, Palmer L, Panaro M, Perez‐Reyes E, Pertwee R, Pike J, Pin J, Pintor S, Plant L, Poyner, Prossnitz E, Pyne S, Ren D, Richer J, Rondard P, Ross R, Sackin H, Safi R, Sanguinetti M, Sartorius C, Segaloff D, Sladek F, Stewart G, Stoddart L, Striessnig J, Summers R, Takeda Y, Tetel M, Toll L, Trimmer J, Tsai M, Tsai S, Tucker S, Usdin T, Vilargada J, Vore M, Ward D, Waxman S, Webb P, Wei A, Weigel N, Willars G, Winrow C, Wong S, Wulff H, Ye R, Young M, Zajac J. The Concise Guide to PHARMACOLOGY 2015/16: Overview. British Journal Of Pharmacology 2015, 172: 5729-5743. PMID: 26650438, PMCID: PMC4718217, DOI: 10.1111/bph.13347.Peer-Reviewed Original ResearchConceptsBest available pharmacological toolsOfficial IUPHAR classificationAvailable pharmacological toolsDrug targetsIon channelsG protein-coupled receptorsHuman drug targetsLigand-gated ion channelsProtein-coupled receptorsVoltage-gated ion channelsNomenclature guidanceIUPHAR-DBMajor pharmacological targetCatalytic receptorsOpen access knowledgebaseNuclear hormone receptorsPharmacological targetsPharmacological toolsHormone receptorsNC-IUPHARPrevious GuidesReceptorsLandscape formatConcise guideRelated targetsNeurology—the next 10 years
Baron R, Ferriero D, Frisoni G, Bettegowda C, Gokaslan Z, Kessler J, Vezzani A, Waxman S, Jarius S, Wildemann B, Weller M. Neurology—the next 10 years. Nature Reviews Neurology 2015, 11: 658-664. PMID: 26503922, DOI: 10.1038/nrneurol.2015.196.Peer-Reviewed Original ResearchContactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy
Doppler K, Appeltshauser L, Krämer HH, Ng JK, Meinl E, Villmann C, Brophy P, Dib-Hajj SD, Waxman SG, Weishaupt A, Sommer C. Contactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy. PLOS ONE 2015, 10: e0134274. PMID: 26218529, PMCID: PMC4517860, DOI: 10.1371/journal.pone.0134274.Peer-Reviewed Original ResearchConceptsMultifocal motor neuropathyMotor neuropathyContactin-1Neurofascin 155Multifocal motor neuropathy patientsChronic inflammatory demyelinating polyneuropathyInflammatory demyelinating polyneuropathySubgroup of patientsNeurofascin-186Enzyme-linked immunosorbentHuman embryonic kidney 293 cellsDemyelinating polyneuropathyAuto antibodiesEmbryonic kidney 293 cellsMuscle weaknessNeuropathy patientsPatient seraConduction blockParanodal proteinsNeuropathyPatientsKidney 293 cellsIgMSerumDifferent assays
2014
Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy
Oliva MK, McGarr TC, Beyer BJ, Gazina E, Kaplan DI, Cordeiro L, Thomas E, Dib-Hajj SD, Waxman SG, Frankel WN, Petrou S. Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy. Neurobiology Of Disease 2014, 67: 180-190. PMID: 24657915, PMCID: PMC4298829, DOI: 10.1016/j.nbd.2014.03.007.Peer-Reviewed Original Research
2012
The NaV1.7 sodium channel: from molecule to man
Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The NaV1.7 sodium channel: from molecule to man. Nature Reviews Neuroscience 2012, 14: 49-62. PMID: 23232607, DOI: 10.1038/nrn3404.Peer-Reviewed Original ResearchConceptsDorsal hornPain disordersNerve endingsNociceptive dorsal root ganglion (DRG) neuronsPainful small fiber neuropathyDorsal root ganglion neuronsVoltage-gated sodium channel Nav1.7Small fiber neuropathyTreatment of painFree nerve endingsSecond-order neuronsSmall molecule blockersSodium channel Nav1.7Function mutationsOlfactory sensory neuronsProbability of neuronsNav1.7 sodium channelSuperficial laminaeGanglion neuronsRisk factorsSympathetic neuronsSlow depolarizationSpinal cordCardiac deficitsSensory neuronsStructural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Yang Y, Dib-Hajj SD, Zhang J, Zhang Y, Tyrrell L, Estacion M, Waxman SG. Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel. Nature Communications 2012, 3: 1186. PMID: 23149731, PMCID: PMC3530897, DOI: 10.1038/ncomms2184.Peer-Reviewed Original ResearchGain-of-function Nav1.8 mutations in painful neuropathy
Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. Gain-of-function Nav1.8 mutations in painful neuropathy. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 19444-19449. PMID: 23115331, PMCID: PMC3511073, DOI: 10.1073/pnas.1216080109.Peer-Reviewed Original ResearchConceptsPainful peripheral neuropathySmall fiber neuropathyPainful neuropathyPeripheral neuropathyPainful small fiber neuropathyDorsal root ganglion neuronsSodium channelsApparent underlying causePeripheral nerve axonsDRG neuronsGanglion neuronsNeuropathyNerve axonsUnderlying causeFunction variantsCurrent clampPatientsPotential pathogenicityNeuronsMutationsHyperexcitabilityAxonsResponseGenetic aspects of sodium channelopathy in small fiber neuropathy
Hoeijmakers J, Merkies I, Gerrits M, Waxman S, Faber C. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clinical Genetics 2012, 82: 351-358. PMID: 22803682, DOI: 10.1111/j.1399-0004.2012.01937.x.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyEtiology of SFNSmall-diameter peripheral axonsIntraepidermal nerve fiber densityDorsal root ganglion neuronsAbnormal thermal thresholdsNerve fiber densityQuantitative sensory testingUnmyelinated C-fibersSFN patientsAutonomic dysfunctionNeuropathic painAδ fibersGanglion neuronsC-fibersPeripheral axonsSensory testingSpecific treatmentSodium channelopathiesApparent causeFiber densitySodium channelsLogical targetNeuropathyPain